Anti-apoptotic Bcl-2 proteins are associated with a number of diseases. There is therefore an existing need in the therapeutic arts for compounds that inhibit the activity of anti-apoptotic Bcl-2 proteins. The Bcl-2 family of proteins are the key regulators of mitochondria-dependent apoptosis in nucleated cells and consists of both anti-apoptotic (Bcl-xL, Bcl-2, Bcl-w, A1, Mcl-1) and pro-apoptotic (Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, Puma) members
Generally, the expression of Bcl-2 protein is associated with many physiologic functions, including the inhibition of apoptosis in the body, in some cases resulting in proliferation of cells affected by the Bcl-2 inhibition. As such, inhibition of Bcl-2 protein may reduce cell proliferation, leading to improved outcomes related to the treatment and prevention of cancer.
Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, and the like is described in commonly-owned PCT US 2004/36770, published as WO 2005/049593, and PCT US 2004/37911, published as WO 2005/024636.